The goal of this project is to elucidate the role of T-regulatory cells in the immunopathology of SIV disease. Abundant evidence suggests that generalized, chronic immune activation is an important cause of naive T-cell depletion and (immune dysfunction. Natural and adaptive T-regulatory cells can suppress immune activation in vitro and in vivo. We hypothesize that T-regulatory cells can slow the progression of SIV and HIV disease by moderating generalized, chronic immune activation. The following Specific Aims will be pursued: 1. Assess natural T-regulatory cells in the blood and lymphoid organs of fetal, infant, juvenile, and adult macaques. Candidate natural T-reg populations will be isolated from macaque blood and tissue samples, then characterized. The distribution of T-regs as a function of age will be described. 2. Assess T-regulatory cells in SIV-infected macaques. We test the number and function of natural T-regs in infected macaques, as well as the possibility that macaques develop adaptive T-regulatory responses to SIV. We hypothesize that more T-regs are correlated with a reduction in measures of immune activation. 3. Measure the influence of an expanded T-reg population on SIV disease progression. Natural T-regs will be expanded in vitro and then reinfused either before or after infection with SIVmac239. Markers of disease progression, immune responses to SIV, and inflammation will be studied for at least six months after infection. Successful completion of these Aims will provide a new understanding of T-reg biology in non-human primates and the possible importance of these cells in SIV disease progression.